Abstract
Sequence analysis revealed a strong homology between the ligand-binding domain (LBD) of the human mineralocorticoid receptor (hMR) and glucocorticoid receptor (hGR). Nevertheless, steroids with bulky C11-substituents bind to hGR, unlike hMR. In this report, a mutant hMR, in which the residue Ala-773 facing the C11 steroid position was replaced by a glycine (A773G), was assayed for its capacity to bind steroids, to interact with receptor coactivators, and to stimulate transcription. The capacity of A773G to bind aldosterone and C11-substituted spirolactones was the same as that of the wild-type receptor. The agonist properties of aldosterone, as well as the antagonist feature of compounds bearing a 11β-allenyl group and a C17-ketone function, remain unchanged. In contrast, C11-substituted steroids with a 17γ-lactonic ring displayed antagonist properties with hMR and acted as potent agonists with A773G. An agonist-dependent hMR interaction with SRC-1 was observed for both the wild-type and the mutant receptors. The hMR activation process is discussed in the light of the hMR-LBD homology model based on the structural data of the human progesterone receptor LBD.
Footnotes
- Received March 9, 2000.
- Accepted June 23, 2000.
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Send reprint requests to: Gilles Auzou, INSERM U439, 70 rue de Navacelles, 34090 Montpellier, France. E-mail:auzou{at}montp.inserm.fr
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↵1 Considered jointly as first authors.
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This work was supported by INSERM (APEX 9834, MERO). This work was presented as a poster to the Forefront meeting of the International Society of Nephrology: “News in Aldosterone Action” Château de Montvillargenne, Paris, France, August 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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